title: Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.
abstract: Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [(3)H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [(3)H]5-HT and an elevated number of [(3)H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus.
authors.affiliation: Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Csölle
authors.forename: Mária
authors.initials: M
authors.lastname: Baranyi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Zsilla
authors.forename: Agnes
authors.initials: A
authors.lastname: Kittel
authors.forename: Flóra
authors.initials: F
authors.lastname: Gölöncsér
authors.forename: Peter
authors.initials: P
authors.lastname: Illes
authors.forename: Edit
authors.initials: E
authors.lastname: Papp
authors.forename: E Sylvester
authors.initials: ES
authors.lastname: Vizi
authors.forename: Beáta
authors.initials: B
authors.lastname: Sperlágh
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D059445:Anhedonia; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017353:Gene Deletion; D018698:Glutamic Acid / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency*; D012701:Serotonin / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D008070:Lipopolysaccharides; D058486:Receptors, Purinergic P2X7; D012701:Serotonin; D018698:Glutamic Acid; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate